Multimodal treatment for resectable neuroendocrine carcinoma of the cervix.

Non-metastatic neuroendocrine carcinoma of the cervix (NECC) is a rare and aggressive disease. Lacking prospective studies, the optimal multimodal treatment approach has not yet been clearly defined. This study aims to assess the clinical outcomes of patients with non-metastatic NECC treated with surgery and (neo)adjuvant chemotherapy, according to pathologic prognostic factors and multimodal treatments received. We retrospectively examined data from patients with non-metastatic NECC candidate to receive surgery and (neo)adjuvant chemotherapy and discussed at the European Institute of Oncology's Multidisciplinary Neuroendocrine Tumor Board, between January 2003 and December 2021. Primary endpoints were event-free survival and overall survival. A total of 27 consecutive patients were evaluated, 15 with early stage NECC and 12 with a locally advanced NECC. Eight patients received neoadjuvant and 19 adjuvant platinum-based chemotherapy; 14 received adjuvant pelvic radiotherapy, half with external-beam radiation therapy alone, and half combined with brachytherapy. No patients progressed or relapsed during (neo)adjuvant chemotherapy. The median event-free survival was 21.1 months and the median overall survival was 33.0 months. Pathological FIGO stage ≥ IIB, adjuvant external-beam radiation therapy with or without brachytherapy emerged as significant and independent prognostic factors for event-free survival. Brachytherapy was also prognostic for overall survival. Non-metastatic NECC requires a multimodal approach, mainly weighted on the FIGO stage. The addition of brachytherapy should be considered, especially in patients with locally advanced disease. Because of the scarcity of robust clinical data, treatment strategy should be discussed in multidisciplinary board, taking into account patient.

Endometrial stromal tumors of the uterus: Epidemiology, pathological and biological features, treatment options and clinical outcomes.

Endometrial stromal tumors (EST) are uterine mesenchymal tumors, which histologically resemble endometrial stroma of the functioning endometrium. The majority of EST are malignant tumors classified as low-grade endometrial stromal sarcoma (LG-ESS), high-grade endometrial stromal sarcoma (HG-ESS), and undifferentiated uterine sarcoma (UUS). Overall, ESTs are rare malignancies, with an annual incidence of approximately 0.30 per 100'000 women, mainly affecting peri- or postmenopausal women. The most common genetic alteration identified in LG-ESS is the JAZF1-SUZ12 rearrangement, while t(10;17)(q23,p13) translocation and BCOR gene abnormalities characterize two major subtypes of HG-ESS. The absence of specific genetic abnormalities is the actual hallmark of UUS. Unlike HG-ESSs, LG-ESSs usually express estrogen and progesterone receptors. Total hysterectomy without morcellation and bilateral salpingo-oophorectomy (BSO) is the first-line treatment of early-stage LG-ESS. Ovarian preservation, fertility-sparing treatment, and adjuvant hormonal therapy ± radiotherapy may be an option in selected cases. In advanced or recurrent LG-ESS, surgical cytoreduction followed by hormonal treatment, or vice versa, are acceptable treatments. The standard treatment for apparently early-stage HG-ESS and UUS is total hysterectomy without morcellation with BSO. Ovarian preservation and adjuvant chemotherapy ± radiotherapy may be an option. In advanced or recurrent HG-ESS, surgical cytoreduction and neoadjuvant or adjuvant chemotherapy can be considered. Alternative treatments, including biological agents and immunotherapy, are under investigation. LG-ESSs are indolent tumor with a 5-year overall survival (OS) of 80-100% and present as stage I-II at diagnosis in two third of patients. HG-ESSs carry a poor prognosis, with a median OS ranging from 11 to 24 months, and 70% of patients are in stage III-IV at presentation. UUS median OS ranges from 12 to 23 months and, at diagnosis, 70% of patients are in stage III-IV. The aim of this review is to assess the clinical, pathological, and biological features and the therapeutic options for malignant ESTs.

Advanced low grade serous ovarian cancer: A retrospective analysis of surgical and chemotherapeutic management in two high volume oncological centers.

Simple summary: Low-grade serous ovarian cancer (LGSOC) represents an uncommon histotype of serous ovarian cancer (accounting for approximately 5% of all ovarian cancer) with a distinct behavior compared to its high-grade serous counterpart, characterized by a better prognosis and low response rate to chemotherapeutic agents. Similar to high-grade serous ovarian cancer, cytoreductive surgery is considered crucial for patient survival. This retrospective study aimed to analyze the outcomes of women affected by advanced stages (III-IV FIGO) of LGSOC from two high-volume oncological centers for ovarian neoplasm. In particular, we sought to evaluate the impact on survival outcomes of optimal cytoreductive surgery [i.e., residual disease (RD) <10 mm at the end of surgery]. The results of our work confirm the role of complete cytoreduction (i.e., no evidence of disease after surgery) in the survival of patients and even the positive prognostic role of a minimal RD (i.e., <10 mm), whenever complete cytoreduction cannot be achieved. Background: Low-grade serous ovarian cancer (LGSOC) is a rare entity with different behavior compared to high-grade serous (HGSOC). Because of its general low chemosensitivity, complete cytoreductive surgery with no residual disease is crucial in advanced stage LGSOC. We evaluated the impact of optimal cytoreduction on survival outcome both at first diagnosis and at recurrence. Methods: We retrospectively studied consecutive patients diagnosed with advanced LGSOCs who underwent cytoreductive surgery in two oncological centers from January 1994 to December 2018. Survival curves were estimated by the Kaplan-Meier method, and 95% confidence intervals (95% CI) were estimated using the Greenwood formula. Results: A total of 92 patients were included (median age was 47 years, IQR 35-64). The median overall survival (OS) was 142.3 months in patients with no residual disease (RD), 86.4 months for RD 1-10 mm and 35.2 months for RD >10 mm (p = 0.002). Progression-free survival (PFS) was inversely related to RD after primary cytoreductive surgery (RD = 0 vs RD = 1-10 mm vs RD >10 mm, p = 0.002). On multivariate analysis, RD 1-10 mm (HR = 2.30, 95% CI 1.30-4.06, p = 0.004), RD >10 mm (HR = 3.89, 95% CI 1.92-7.88, p = 0.0004), FIGO stage IV (p = 0.001), and neoadjuvant chemotherapy (NACT) (p = 0.010) were independent predictors of PFS. RD >10 mm (HR = 3.13, 95% CI 1.52-6.46, p = 0.004), FIGO stage IV (p <0.0001) and NACT (p = 0.030) were significantly associated with a lower OS. Conclusions: Optimal cytoreductive surgery improves survival outcomes in advanced stage LGSOC s . When complete debulking is impossible, a RD <10 mm confers better OS compared to an RD >10 mm in this setting of patients.

Clear cell carcinoma of the ovary: Epidemiology, pathological and biological features, treatment options and clinical outcomes.

Clear cell carcinoma of the ovary is a rare and distinct histotype of epithelial ovarian carcinomas. Women diagnosed with clear cell carcinomas are usually younger and diagnosed at earlier stages than those with the most common high-grade serous histology. Endometriosis is considered a main risk factor for the development of clear cell carcinoma of the ovary, and it can be considered a precursor of of this tumor, as it is identified in more than 50% of patients with clear cell carcinoma. Different molecular pathways and alterations heve been identified in ovarian clear cell carcinoma, including the most common mutations of AT-rich interaction domain 1A [ARID1A] and phosphatidylinositol-4,5-bisphosphate 3-kinase [PIK3] catalytic subunit alpha [PIK3CA]. The prognosis of patients at early stage is favorable, while patients with advanced or recurrent disease experience a poor oncologic outcomes. Despite a lower rate of responses due to an intrinsic chemoresistance, the treatment strategy for advanced disease resembles the treatment of high-grade serous carcinoma, which includes aggressive cytoreductive surgery and platinum-based chemotherapy. For this reason, the role of adjuvant chemotherapy in patients with stage I disease undergoing complete surgical staging is still under debate. Alternative treatments, including biological agents that target different pathways constitute the most promising treatment strategies, and well-designed, collaborative international trials should be designed in order to improve the oncologic outcomes and the quality of life of patients with this aggressive disease.

The Adaptive and Innate Immune Cell Landscape of Uterine Leiomyosarcomas.

Reactivation of the anti-tumor response has shown substantial progress in aggressive tumors such as melanoma and lung cancer. Data on less common histotypes are scanty. Immune checkpoint inhibitor therapy has been applied to few cases of uterine leiomyosarcomas, of which the immune cell composition was not examined in detail. We analyzed the inflammatory infiltrate of 21 such cases in high-dimensional, single cell phenotyping on routinely processed tissue. T-lymphoid cells displayed a composite phenotype common to all tumors, suggestive of antigen-exposure, acute and chronic exhaustion. To the contrary, myelomonocytic cells had case-specific individual combinations of phenotypes and subsets. We identified five distinct monocyte-macrophage cell types, some not described before, bearing immunosuppressive molecules (TIM3, B7H3, VISTA, PD1, PDL1). Detailed in situ analysis of routinely processed tissue yields comprehensive information about the immune status of sarcomas. The method employed provides equivalent information to extractive single-cell technology, with spatial contexture and a modest investment.

Placental site trophoblastic tumor and epithelioid trophoblastic tumor: Clinical and pathological features, prognostic variables and treatment strategy.

Placental site trophoblastic tumor [PSTT] and epithelioid trophoblastic tumor [ETT] are the rarest gestational trophoblastic neoplasias, developing from intermediate trophoblast of the implantation site and chorion leave, respectively. PSTT and ETT share some clinical-pathological features, such as slow growth rates, early stage at presentation, relatively low ßhCG levels and poor response to chemotherapy. The mortality rate ranges from 6.5% to 27% for PSTT and from 10% to 24.2% for ETT. Advanced stage, long interval between antecedent pregnancy and diagnosis, and presence of clear cells are the independent prognostic variables for PSTT, and they may be similar for ETT. Hysterectomy can represent the only therapy for early disease, whereas adjuvant chemotherapy should be reserved to patients with poor risk factors, such as an interval from the antecedent pregnancy >4 years, deep myometrial invasion or serosal involvement. Few cases of fertility-sparing treatment in young women have been reported. An individualized multidisciplinary approach, including chemotherapy and debulking surgery with abdominal and/or extra-abdominal procedures, is warranted for advanced disease. EP/EMA and TP/TE are the preferred regimens in this setting. Immunohistochemistry has sometimes shown expression of EGFR, VEGF, MAPK, PDGF-R and PD-L1, and therefore investigational studies on biological agents targeting these molecules are strongly warranted for chemotherapy resistant-disease.

Melanoma of the lower genital tract: Prognostic factors and treatment modalities.

Primary melanomas originating from the gynecological tract are rare and aggressive cancers. The vulva is the most frequent site (70%), followed by vagina and more rarely by cervix. The clinical outcome of patients with female genital tract melanoma is very poor, with a 5-year overall survival (OS) of 37-50% for vulvar, 13-32% for vaginal, and approximately 10% for cervical melanoma. In this systematic review, we analyzed the pathogenesis and the different factors influencing the prognosis of melanomas of the lower genital tract, with particular emphasis on biologic variables that may influence new therapeutic approaches. We evaluated the different treatment modalities described in the literature, in order to offer a possible algorithm that may help the clinicians in diagnosing and treating patients with these uncommon malignancies.

Adjuvant chemoradiotherapy versus radiotherapy alone for women with high-risk endometrial cancer (PORTEC-3): final results of an international, open-label, multicentre, randomised, phase 3 trial.

BACKGROUND: Although women with endometrial cancer generally have a favourable prognosis, those with high-risk disease features are at increased risk of recurrence. The PORTEC-3 trial was initiated to investigate the benefit of adjuvant chemotherapy during and after radiotherapy (chemoradiotherapy) versus pelvic radiotherapy alone for women with high-risk endometrial cancer. METHODS: PORTEC-3 was an open-label, international, randomised, phase 3 trial involving 103 centres in six clinical trials collaborating in the Gynaecological Cancer Intergroup. Eligible women had high-risk endometrial cancer with FIGO 2009 stage I, endometrioid-type grade 3 with deep myometrial invasion or lymph-vascular space invasion (or both), endometrioid-type stage II or III, or stage I to III with serous or clear cell histology. Women were randomly assigned (1:1) to receive radiotherapy alone (48·6 Gy in 1·8 Gy fractions given on 5 days per week) or radiotherapy and chemotherapy (consisting of two cycles of cisplatin 50 mg/m2 given during radiotherapy, followed by four cycles of carboplatin AUC5 and paclitaxel 175 mg/m2) using a biased-coin minimisation procedure with stratification for participating centre, lymphadenectomy, stage of cancer, and histological type. The co-primary endpoints were overall survival and failure-free survival. We used the Kaplan-Meier method, log-rank test, and Cox regression analysis for final analysis by intention to treat and adjusted for stratification factors. The study was closed on Dec 20, 2013, after achieving complete accrual; follow-up is ongoing. PORTEC-3 is registered with ISRCTN, number ISRCTN14387080, and ClinicalTrials.gov, number NCT00411138. RESULTS: 686 women were enrolled between Nov 23, 2006, and Dec 20, 2013. 660 eligible patients were included in the final analysis, of whom 330 were assigned to chemoradiotherapy and 330 were assigned to radiotherapy. Median follow-up was 60·2 months (IQR 48·1-73·1). 5-year overall survival was 81·8% (95% CI 77·5-86·2) with chemoradiotherapy versus 76·7% (72·1-81·6) with radiotherapy (adjusted hazard ratio [HR] 0·76, 95% CI 0·54-1·06; p=0·11); 5-year failure-free survival was 75·5% (95% CI 70·3-79·9) versus 68·6% (63·1-73·4; HR 0·71, 95% CI 0·53-0·95; p=0·022). Grade 3 or worse adverse events during treatment occurred in 198 (60%) of 330 who received chemoradiotherapy versus 41 (12%) of 330 patients who received radiotherapy (p<0·0001). Neuropathy (grade 2 or worse) persisted significantly more often after chemoradiotherapy than after radiotherapy (20 [8%] women vs one [1%] at 3 years; p<0·0001). Most deaths were due to endometrial cancer; in four patients (two in each group), the cause of death was uncertain. One death in the radiotherapy group was due to either disease progression or late treatment complications; three deaths (two in the chemoradiotherapy group and one in the radiotherapy group) were due to either intercurrent disease or late treatment-related toxicity. INTERPRETATION: Adjuvant chemotherapy given during and after radiotherapy for high-risk endometrial cancer did not improve 5-year overall survival, although it did increase failure-free survival. Women with high-risk endometrial cancer should be individually counselled about this combined treatment. Continued follow-up is needed to evaluate long-term survival. FUNDING: Dutch Cancer Society, Cancer Research UK, National Health and Medical Research Council Project Grant and Cancer Australia, L'Agenzia Italiana del Farmaco, and Canadian Cancer Society Research Institute.

Multidisciplinary approach in the management of advanced ovarian cancer patients: A personalized approach. Results from a specialized ovarian cancer unit.

OBJECTIVE: The aim of the present study was to evaluate the impact of a multidisciplinary approach in patients' selection with advanced ovarian cancer (AOC) for different therapeutic strategies. METHODS: Patients referred at our institution between 2009 and 2012 for AOC were included. Primary multidisciplinary evaluation was performed in all patients. Different strategies included: 1. patients referred to primary neoadjuvant chemotherapy (NACT) and interval surgery (IDS) (group A); 2. patients considered for surgical exploration. After surgical exploration, patients were either considered for primary debulking (PDS; group B), or NACT (group C). RESULTS: A total of 363 patients were included. Of 38 patients (10.5%) in group A, 24 (63%) had sovradiaphragmatic/multiple liver metastases; 14 (37%) were excluded for PDS for anestehesiologic/medical reasons. Of 325 (89.5%) considered for surgical exploration, 295 (91%; group B) had primary surgery with debulking intent (N: 277) and were cytoreduced to no macroscopic disease (R0: N:200; 68%) o minimal RD<5mm (R1: N:77; 26%) or palliative intent (N:18; 6%); 30 (9%; group C) were referred for NACT. Of those, 27 (90%) underwent IDS, 3 had progressive disease. Overall survival (OS) and progression free survival (PFS) was different between the groups: OS: Group A: 34months; Group B: 59months; Group C: 29months; p<0.001. PFS: Group A: 10months; Group B; 21months; Group C: 12months; p<0.001. CONCLUSIONS: A multidisciplinary approach to patients referred to a tertiary center with AOC allows optimization of the treatment strategy, based on patients' characteristics (age, performance/nutritional status, comorbidities, functional status) and tumor diffusion (evaluated pre- and intraoperatively).

Neuroendrocrine tumors of the uterine cervix: A therapeutic challenge for gynecologic oncologists.

Neuroendocrine tumors (NETs) are aggressive diseases developing from neuroendocrine cells that most frequently involve the gastro-entero-pancreatic tract and the lung, but more rarely are found in almost all body tissues. Limited biological and clinical data are currently available for NETs in uncommon sites, such as female genital tract. NETs represent 0.9% to 1.5% of the tumors of the uterine cervix. They are more likely to have lymph-vascular space invasion and lymph node involvement, and to develop local and distant relapses when compared with the mostly common cervical squamous cell carcinomas or adenocarcinomas. Positive immunostaining for synaptophysin, chromogranin, CD56, and neuron-specific enolase is often detected in cervical NETs . The most recent editions of the World Health Organization Classification of Gynecologic Tract tumors grouped cervical carcinoid tumor and atypical carcinoid tumor into low-grade NETs and cervical small cell neuroendocrine carcinoma and large cell neuroendocrine carcinoma into high-grade NETs. High-risk HPV DNA is detected in almost all cervical high-grade NETs. No treatment guidelines, based on prospective, well-designed clinical trials, are currently available due to the rarity of these tumors. Many authors have reported different multimodality approaches, mainly derived from NETs of the lung. These usually consist in radical hysterectomy followed by adjuvant chemotherapy or concurrent chemoradiation for early stage disease, definitive concurrent chemoradiation sometimes preceded by neoadjuvant chemotherapy and followed by adjuvant chemotherapy for locally advanced disease, and palliative chemotherapy for metastatic disease. In this systematic review, we address the histologic classification of cervical NETs, analyze their pathogenesis and overall prognosis, and evaluate the different treatment modalities described in the literature, in order to offer a possible algorithm that may help the clinicians in diagnosing and treating patients with these uncommon and aggressive malignancies.

European Society of Gynaecological Oncology (ESGO) Guidelines for Ovarian Cancer Surgery.

METHODS: The European Society of Gynaecological Oncology council nominated an international multidisciplinary development group made of practicing clinicians who have demonstrated leadership and interest in the care of ovarian cancer (20 experts across Europe). To ensure that the statements are evidence based, the current literature identified from a systematic search has been reviewed and critically appraised. In the absence of any clear scientific evidence, judgment was based on the professional experience and consensus of the development group (expert agreement). The guidelines are thus based on the best available evidence and expert agreement. Before publication, the guidelines were reviewed by 66 international reviewers independent from the development group including patients representatives. RESULTS: The guidelines cover preoperative workup, specialized multidisciplinary decision making, and surgical management of diagnosed epithelial ovarian, fallopian tube, and peritoneal cancers. The guidelines are also illustrated by algorithms.

European Society of Gynaecologic Oncology Quality Indicators for Advanced Ovarian Cancer Surgery.

OBJECTIVES: The surgical management of advanced ovarian cancer involves complex surgery. Implementation of a quality management program has a major impact on survival. The goal of this work was to develop a list of quality indicators (QIs) for advanced ovarian cancer surgery that can be used to audit and improve the clinical practice. This task has been carried out under the auspices of the European Society of Gynaecologic Oncology (ESGO). METHODS: Quality indicators were based on scientific evidence and/or expert consensus. A 4-step evaluation process included a systematic literature search for the identification of potential QIs and the documentation of scientific evidence, physical meetings of an ad hoc multidisciplinarity International Development Group, an internal validation of the targets and scoring system, and an external review process involving physicians and patients. RESULTS: Ten structural, process, or outcome indicators were selected. Quality indicators 1 to 3 are related to achievement of complete cytoreduction, caseload in the center, training, and experience of the surgeon. Quality indicators 4 to 6 are related to the overall management, including active participation to clinical research, decision-making process within a structured multidisciplinary team, and preoperative workup. Quality indicator 7 addresses the high value of adequate perioperative management. Quality indicators 8 to 10 highlight the need of recording pertinent information relevant to improvement of quality. An ESGO-approved template for the operative report has been designed. Quality indicators were described using a structured format specifying what the indicator is measuring, measurability specifications, and targets. Each QI was associated with a score, and an assessment form was built. CONCLUSIONS: The ESGO quality criteria can be used for self-assessment, for institutional or governmental quality assurance programs, and for the certification of centers. Quality indicators and corresponding targets give practitioners and health administrators a quantitative basis for improving care and organizational processes in the surgical management of advanced ovarian cancer.

Treatment options for pregnant women with ovarian tumors.

Diagnosis of ovarian mass during pregnancy is a rare event. Treatment of ovarian malignancies during pregnancy depends on histology, grade, stage, and gestational weeks. When possible, surgical excision is indicated, and sometimes, fertility-sparing surgery is recommended. Administration of systemic treatment before or after surgery is indicated as in nonpregnant women. Preliminary data suggest that platinum salts and taxanes are safe during pregnancy. Management of ovarian tumors in pregnancy requires a multidisciplinary approach to guarantee an optimal treatment for the mother and the fetus.

Adjuvant chemotherapy in stage I-II uterine leiomyosarcoma: a multicentric retrospective study of 140 patients.

OBJECTIVE: About 50-60% of patients with stage I-II uterine leiomyosarcoma (ULMS), primarily treated with surgery, relapse and die from progressive disease. In this retrospective study we describe the impact of adjuvant chemotherapy in this subset of patients. METHODS: 140 women treated from 1976 to 2011 were included in the study. Univariate and multivariate analysis were used to test the association of clinical features and adjuvant treatments with overall survival (OS) and disease-free survival (DFS). RESULTS: 62 women did not receive any further treatment after hysterectomy, 14 had radiotherapy (RT), 52 chemotherapy and 12 chemo-radiotherapy. Chemotherapy based on doxorubicin and ifosfamide combination was used in 54 cases. After a median follow-up of 63months, 87 women (62%) have relapsed, and 62 (44%) have died. The vast majority of patients who relapsed had distant recurrences (72%). The 5year median DFS and OS were 43% and 64% respectively. After 5years of follow up 68.7% of women treated with chemotherapy (±RT) vs 65.6% of patients only observed were alive (p=0.521). In the univariate analysis no factors had a statistical impact on DFS, while number of mitosis (>20×10HPF), age (>60years) and adjuvant radiotherapy were found as negative prognostic factors for OS. In the multivariate analysis only mitosis and age remained significant for OS. CONCLUSION: Adjuvant chemotherapy was not associated with a significant survival benefit and should not be considered as standard of care for patients with stage I-II ULMS until randomized clinical studies will give further information.

Ulipristal acetate: a novel pharmacological approach for the treatment of uterine fibroids.

Uterine fibroids are the most common benign tumors of the female genital tract. The management of symptomatic fibroids has traditionally been surgical; however, alternative pharmacological approaches have been proposed to control symptoms. To date, gonadotropin-releasing hormone analogs are the only available drugs for the preoperative treatment of fibroids. However, the US Food and Drug Administration recently authorized ulipristal acetate (UPA), an oral selective progesterone-receptor modulator, for the same indication. UPA is a new, effective, and well-tolerated option for the preoperative treatment of moderate and severe symptoms of uterine fibroids in women of reproductive age. According to clinical data, UPA shows several advantages: it is faster than leuprolide in reducing the fibroid-associated bleeding, it significantly improves hemoglobin and hematocrit levels in anemic patients, and it grants a significant reduction in the size of fibroids, which lasts for at least 6 months after the end of the treatment. Furthermore, UPA displays a better tolerability profile when compared to leuprolide; in fact, it keeps estradiol levels at mid follicular phase range, thereby reducing the incidence of hot flushes and exerting no impact on bone turnover. On the grounds of this evidence, the administration of 5 mg/day ulipristal acetate for 3 months is suggested for different patient categories and allows for planning a treatment strategy tailored to meet an individual patient's needs.

Tissue genotyping of 37 in situ and invasive cervical cancer with a concomitant negative HC2 HPV DNA test.

OBJECTIVE: The rare occurrence of histology-proven cervical intraepithelial neoplasia grade 3 (CIN 3) or invasive cancer with a negative HC2 result is known. Tissue blocks of 37 cases of histology-diagnosed CIN 3+ with a concomitant negative HC2 test were genotyped to investigate the human papillomavirus (HPV) status within the lesion. METHODS: We considered 1,976 cervical excision specimens performed with concomitant HC2 test. Of these, 37 histology-confirmed CIN 3+ resulted HC2 negative. Thirty-three paraffin blocks, derived by the cervical excision, could be genotyped for high- (HR) and low-risk (LR) HPV genotypes. RESULTS: Detailed histology showed 30 CIN 3, 2 squamous cell invasive carcinomas, and 5 invasive adenocarcinomas. One specimen resulted not amplifiable at the genotyping. Twenty-two cases (68.7%) were positive for HR-HPV types, either in single (n = 17) or multiple HR-HPV infection (n = 5). Most of the HR-HPVs found were 16 or 18. Ten cases (31.3%) were negative for HR-HPV types; 5 of these were positive for probable HR-HPV types, not detectable with HC2 HR-probes, 1 was positive to LR-HPV types, while 1 had HPV-69/71. Three cases were negative for HPV DNA, either high or low risk. CONCLUSIONS: Of the rare cases of CIN 3+ lesions with concomitant negative HC2 test, 69% are true failures in HR-HPV detection. One third of HC2-negative CIN 3+ is related to the presence of other HPV genotypes not covered by the HC2 panel or to undetectable HPV in the lesion; both these rare occurrences were already described in large cancer series and partially explain the occurrence of HPV-negative CIN 3+.

External validation of a prognostic nomogram for overall survival in women with uterine leiomyosarcoma.

BACKGROUND: There is no validated system to identify prognostically distinct cohorts of women with uterine leiomyosarcoma (ULMS). By using an independent, pooled, multi-institutional, international patient cohort, the authors validated a recently proposed ULMS nomogram. METHODS: The ULMS nomogram incorporated 7 clinical characteristics (age, tumor size, tumor grade, cervical involvement, locoregional metastases, distant metastases, and mitotic index (per 10 high-power fields) to predict overall survival (OS) after primary surgery. Independent cohorts from 2 sarcoma centers were included. Eligible women, at minimum, underwent a hysterectomy for primary, locally advanced, or metastatic ULMS and received part of their care at 1 of the centers between 1994 and 2010. RESULTS: In total, 187 women with ULMS were identified who met the above criteria described above (median age, 51 years; median tumor size, 9 cm; median mitotic index, 20 per 10 high-power fields). Tumors generally were high grade (88%), FIGO stage I or II (61%) without cervical involvement (93%) and without locoregional metastases (77%) or distant metastases (83%). The median OS and the 5-year OS rate were 4.5 years (95% confidence interval, 3.2-5.3 years) and 46%, respectively; and 65 women (35%) remained alive at last follow-up. The nomogram concordance index was 0.67(standard error, 0.02), which was as high as the concordance index from the initial cohort used for nomogram development. The concordance between actual OS and nomogram predictions suggests excellent calibration because predictions were within 1% of actual 5-year OS rates for patients with a predicted 5-year OS of less than 0.68. CONCLUSIONS: The ULMS nomogram was externally validated using independent cohorts. These findings support the international use of the ULMS nomogram prognostic of OS in ULMS.

p16 expression in squamous and trophoblastic lesions of the upper female genital tract.

p16, a surrogate marker for human papillomavirus (HPV) infection, is uniformly present in HPV-related carcinomas. This study aims to further characterize p16 expression in trophoblastic lesions and squamous lesions of the upper female genital tract, as little data exists. p16 immunostaining was performed on sections from ichthyosis uteri (1), primary uterine corpus squamous cell carcinoma (UCSCC) (2), primary ovarian SCC (OSCC) (5; 2 associated with a dermoid cyst), endometrial endometrioid adenocarcinoma with extensive squamous differentiation (EC-SD) (5), ovarian endometrioid adenocarcinoma with extensive squamous differentiation (OC-SD) (4), placental site nodule (5), and placental site trophoblastic tumor (PSTT) (6). We evaluated the percentage of positive cytoplasmic and nuclear staining (focal ≤10%, multifocal=10% to 50%, and diffuse ≥50%) and staining intensity (weak, moderate, and strong). HPV-DNA analysis by polymerase chain reaction was performed on 5 OSCC. Ichthyosis uteri, all UCSCC and 1 OSCC (arising in a dermoid) were negative; the other dermoid-associated OSCC showed focal moderate staining, the remaining OSCC displayed strong (100%), diffuse (2), or multifocal (1) p16 positivity. Three of the 5 EC-SD cases showed strong diffuse staining of the squamous component. The glandular component focally showed strong p16 positivity (2), with variably intense focal staining in 3 cases. The squamous component of all OC-SD showed focal moderate staining, with variable staining of the glandular component. Overall, 3 EC-SD had 80% to 90% p16 positivity. Five of the 5 placental site nodules and 4 of the 6 PSTT showed focal weak staining, whereas 2 PSTT were p16 negative. HPV-DNA analysis was negative in 3 of the 5 OSCC, the other 2 cases being technical failures. p16 is expressed in OSCC and in the squamous and glandular components of EC-SD and OC-SD. As p16 is negative in UCSCC, it may help to identify the origin of SCC diffusely involving the corpus and cervix, and suggests different pathogeneses for SCC of the upper female genital tract, likely to be unrelated to HPV infection. In contrast to earlier data, we found weak and focal p16 expression in trophoblastic lesions. Thus, when considering the differential diagnosis of cervical SCC and trophoblastic lesions, only strong diffuse p16 staining should be considered helpful.